TY - JOUR
T1 - A novel locus for dementia with Lewy bodies
T2 - A clinically and genetically heterogeneous disorder
AU - Bogaerts, Veerle
AU - Engelborghs, Sebastiaan
AU - Kumar-Singh, Samir
AU - Goossens, Dirk
AU - Pickut, Barbara
AU - Van Der Zee, Julie
AU - Sleegers, Kristel
AU - Peeters, Karin
AU - Martin, Jean Jacques
AU - Del-Favero, Jurgen
AU - Gasser, Thomas
AU - Dickson, Dennis W.
AU - Wszolek, Zbigniew K.
AU - De Deyn, Peter P.
AU - Theuns, Jessie
AU - Van Broeckhoven, Christine
N1 - Funding Information:
We are grateful to the participants of this study for their kind cooperation. We also acknowledge the personnel of the VIB Genetic Service Facility (http:// www.vibgeneticservicefacility.be) and the Biobank of the Institute Born-Bunge. J. Searcy helped in obtaining additional data on family G. R. McComb provided hippocampus tissue of the index patient of family G. This study was supported by the Special Research Fund of the University of Antwerp, the Fund for Scientific Research Flanders (FWO-F), the Institute for Science and Technology – Flanders (IWT-F), the Interuniversity Attraction Poles program P5/19 and P6/43 of the Belgian Science Policy Office. The research was in part funded by EU contract LSHM-CT-2003-503330 (APOPIS). P.P.D.D. was funded by the Medical Research Foundation and Neurosearch Antwerp. T.G. was partly sponsored by the German Ministry for Education and Research and the Hertie-Institute for Clinical Brain Research, Tübingen, Germany. The work of D.W.D. and Z.K.W. is funded by the Morris K. Udall Parkinson’s Disease Center of Excellence grant P50 NS40256. V.B. holds a PhD fellowship and S.E., K.S. and J.T. a postdoctoral fellowship of the FWO-F. J.V.D.Z. is holder of a PhD fellowship of the IWT-F. Funding to pay the Open Access publication charges for this article was provided by the Special Research Fund of the University of Antwerp.
PY - 2007/9
Y1 - 2007/9
N2 - Dementia with Lewy bodies (DLB) represents the second most frequent type of neurodegenerative dementia in the elderly. Although most patients have sporadic DLB, a limited number of DLB families have been described, suggesting that genetic factors may contribute to DLB pathogenesis. Here, we describe a three-generation Belgian family with prominent dementia and parkinsonism, consistent with a diagnosis of DLB, that was autopsy confirmed for the index patient. In a genome-wide scan and subsequent finemapping of candidate loci we obtained significant linkage to 2q35-q36 (Z = 3.01 at D2S1242). Segregation analysis defined a candidate region of 9.2 Mb between D2S433 and chr2q36.3-8, adjacent to the previously reported PARK11 locus. In addition, haplotype sharing studies in another DLB family of close geographical origin with similar clinical and neuropathological features highlighted the specificity of a 2q35-q36 haplotype harbouring a pathogenic mutation that causes DLB in the Belgian family. So far, extensive sequence analysis of five candidate genes within the 2q35-q36 region has not revealed a disease-causing mutation. Together, our data re-emphasize the genetic heterogeneity of DLB, and strongly support the existence of a gene for familial DLB on 2q35-q36. Once identified this will be the first novel causal gene for DLB and can be expected to open new avenues for biological studies of the disease process.
AB - Dementia with Lewy bodies (DLB) represents the second most frequent type of neurodegenerative dementia in the elderly. Although most patients have sporadic DLB, a limited number of DLB families have been described, suggesting that genetic factors may contribute to DLB pathogenesis. Here, we describe a three-generation Belgian family with prominent dementia and parkinsonism, consistent with a diagnosis of DLB, that was autopsy confirmed for the index patient. In a genome-wide scan and subsequent finemapping of candidate loci we obtained significant linkage to 2q35-q36 (Z = 3.01 at D2S1242). Segregation analysis defined a candidate region of 9.2 Mb between D2S433 and chr2q36.3-8, adjacent to the previously reported PARK11 locus. In addition, haplotype sharing studies in another DLB family of close geographical origin with similar clinical and neuropathological features highlighted the specificity of a 2q35-q36 haplotype harbouring a pathogenic mutation that causes DLB in the Belgian family. So far, extensive sequence analysis of five candidate genes within the 2q35-q36 region has not revealed a disease-causing mutation. Together, our data re-emphasize the genetic heterogeneity of DLB, and strongly support the existence of a gene for familial DLB on 2q35-q36. Once identified this will be the first novel causal gene for DLB and can be expected to open new avenues for biological studies of the disease process.
KW - 2q35-q36
KW - Autosomal dominant inheritance
KW - Dementia with Lewy bodies
KW - Genetic heterogeneity
KW - Linkage analysis
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U2 - 10.1093/brain/awm167
DO - 10.1093/brain/awm167
M3 - Article
C2 - 17681982
AN - SCOPUS:34548222135
SN - 0006-8950
VL - 130
SP - 2277
EP - 2291
JO - Brain
JF - Brain
IS - 9
ER -